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Abstract:

Stable aerosol solution formulations comprising glycopyrronium bromide
are useful for administration to patients with COPD and other respiratory
conditions.

Claims:

1. A pharmaceutical composition, comprising glycopyrronium bromide
dissolved in an HFA propellant and a co-solvent, wherein said composition
comprises an amount of hydrochloric acid equivalent to 0.005 to 1.0
μg/μl of 1M hydrochloric acid.

2. A composition according to claim 1, wherein said composition comprises
an amount of hydrochloric acid equivalent to 0.18 to 0.32 μg/μl of
1M hydrochloric acid.

3. A composition according to claim 1, wherein the co-solvent is ethanol.

4. A composition according to claim 1, comprising glycopyrronium bromide
in an amount in the range of 0.005 to 0.14% w/w of the composition.

5. A composition according to claim 1, further comprising one or more
pharmaceutically active ingredients selected from the group consisting of
beta-2-agonists, corticosteroids, antimuscarinic agents, and
phosphodiesterase (IV) inhibitors.

6. A composition according to claim 5, comprising formoterol fumarate.

7. A composition according to claim 5, further comprising beclometasone
dipropionate.

8. A metered dose inhaler, comprising a pharmaceutical composition
according to claim 1.

9. A kit-of-parts, comprising a pharmaceutical composition according to
claim 1 and further comprising one or more pharmaceutically active
ingredients for separate, sequential or simultaneous administration,
wherein said pharmaceutically active ingredients are selected from the
group consisting of beta-2-agonists, corticosteroids, antimuscarinic
agents, and phosphodiesterase (IV) inhibitors.

10. A method of filling an aerosol canister with a pharmaceutical
composition according to claim 1, comprising: a) preparing a solution
comprising glycopyrronium bromide, a co-solvent, a mineral acid and
optionally a low volatility component; b) filling an open canister with
the solution; c) placing a valve onto the canister and crimping; and d)
pressure-filling the canister with HFA propellant through the valve.

11. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 1 to a subject in need thereof.

12. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 2 to a subject in need thereof.

13. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 3 to a subject in need thereof.

14. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 4 to a subject in need thereof.

15. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 5 to a subject in need thereof.

16. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 6 to a subject in need thereof.

17. A method for the prevention and/or treatment of a respiratory
disorder, comprising administering an effective amount of a composition
according to claim 7 to a subject in need thereof.

Description:

CROSS REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to European Patent Application No.
09015980.7 filed on Dec. 23, 2009, which is incorporated herein by
reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to pharmaceutical aerosol solution
formulations comprising glycopyrronium bromide, intended for use in
pressurized metered dose inhalers. The present invention further relates
to use of such formulations in the prevention and therapy of respiratory
disorders, including chronic obstructive pulmonary disease (COPD).

[0004] 2. Discussion of the Background

[0005] Glycopyrronium bromide (also known as glycopyrrolate) is a
muscarinic M3 anticholinergic agent used to reduce salivation associated
with administration of certain anaesthetics, and as adjunctive therapy
for peptic ulcers. It has also been reported to be effective in the
treatment of asthmatic symptoms (Hansel et al., Chest, 2005;
128:1974-1979).

[0006] WO 2005/107873 disclose the use of glycopyrrolate for the treatment
of childhood asthma.

[0007] WO 01/76575 discloses a controlled release formulation for
pulmonary delivery of glycopyrrolate. The formulation is intended for use
in treatment of respiratory disease, in particular chronic obstructive
pulmonary disease (COPD). The application focuses on dry powder
formulations suitable for delivery by means of a dry powder inhaler
(DPI).

[0008] One of the drawbacks of DPIs is that insufficient patient
inhalation flow rates may lead to reduced dose delivery and incomplete
deaggregation of the powder, leading to unsatisfactory device
performance. For this reason DPIs are normally used only in older
children and adults. Younger children and other people with inhalation
difficulties can benefit from use of propellant-based aerosol
formulations, administered by pressurized metered dose inhalers (pMDIs).
pMDIs use propellant to expel droplets containing the pharmaceutical
product to the respiratory tract in an aerosol.

[0009] It would be desirable to provide a clinically useful aerosol
product in the form of a solution that delivers the therapeutic benefits
of glycopyrronium bromide in effective and consistent doses over an
extended product lifetime, and ideally without the need for storage under
special conditions of temperature or humidity.

SUMMARY OF THE INVENTION

[0010] Accordingly, it is one object of the present invention to provide
novel pharmaceutical aerosol solution formulations comprising
glycopyrronium bromide, intended for use in pressurized metered dose
inhalers.

[0011] It is another object of the present invention to provide novel
methods for the prevention and therapy of respiratory disorders,
including COPD.

[0012] These and other objects, which will become apparent during the
following detailed description, have been achieved by the inventors'
discovery that pharmaceutical compositions comprising glycopyrronium
bromide dissolved in an HFA propellant, an optional co-solvent, and an
amount of acid sufficient to stabilize the glycopyrronium bromide are
useful for the prevention and therapy of respiratory disorders, including
COPD.

[0013] Additional pharmaceutically active ingredients may also be
included.

[0014] In a further aspect, the present invention provides a pressurized
metered dose inhaler or other container suitable for aerosol delivery,
comprising the pharmaceutical composition of the invention.

[0015] In another aspect, the present invention provides the use of
pharmaceutical compositions as described herein for the therapeutic or
palliative treatment or prevention of respiratory disease conditions,
such as COPD.

[0016] In another aspect, the present invention provides methods for the
therapeutic or palliative treatment or prevention of respiratory disease
conditions, such as COPD.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] A solution formulation of glycopyrronium bromide in HFA propellant
with ethanol as co-solvent was prepared and checked for stability after 3
months following storage under different conditions of temperature and
humidity. One batch was stored under optimal conditions (refrigeration);
the other batches were stored under accelerated degradation conditions of
high temperature and humidity. Although the refrigerated batch remained
stable over the 3 month period, the other batches degraded significantly
over that time-span. This is the first time that glycopyrronium bromide
has been observed to exhibit poor stability in any type of formulation.

[0018] Thus, a simple aerosol solution formulation of glycopyrronium
bromide dissolved in propellant and co-solvent fails to meet the
requirements for practical use, namely that it should be capable of being
carried on the person without refrigeration and yet deliver consistent
dosages of active ingredient.

[0019] The present inventors were able to overcome these stability issues
by inclusion of a specific amount of inorganic acid in the formulation.
In particular, they found that inclusion of an amount of 1M hydrochloric
acid (HCl) in the range of 0.005 to 1.0 μg/μl, preferably
0.099-0.74 μg/μl, and more preferably 0.18-0.32 μg/μl, to the
solution is sufficient to eliminate degradation of glycopyrronium bromide
over an extended period of non-optimal storage, thereby ensuring a
consistent dose of glycopyrronium bromide per actuation of the pMDI
containing the solution formulation.

[0020] Glycopyrronium bromide, chemically defined as
3-[(cyclopentylhydroxy-phenylacetyl)oxy]-1,1-dimethylpyrrolidinium
bromide, has two chiral centers corresponding to four potential different
stereoisomers with configurations (3R,2'R), (3S,2'R), (3R,2'S), and
(3S,2'S). Glycopyrronium bromide in the form of any of these pure
enantiomers or diastereomers or any combination thereof may be used in
practising the present invention. In one embodiment of the present
invention, the
(3S,2'R),(3R,2'S)-3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethylpyr-
rolidinium bromide racemic mixture, also known as glycopyrrolate is
preferred. Glycopyrronium bromide is present in the formulation in an
amount in the range from 0.005 to 0.14% (w/w), preferably from 0.010 to
0.13% (w/w), more preferably from 0.015 to 0.04% (w/w), wherein % (w/w)
means the amount by weight of the component, expressed as percent with
respect to the total weight of the composition.

[0021] Glycopyrrolate is commercially available, and can be synthesized
according to the process described in U.S. Pat. No. 2,956,062 or in
Franko B V and Lunsford C D, J. Med. Pharm. Chem., 2(5), 523-540, 1960.

[0022] The propellant component of the composition may be any
pressure-liquefied propellant and is preferably a hydrofluoroalkane (HFA)
or a mixture of different HFAs, more preferably selected from the group
consisting of HFA134a (1,1,1,2-tetrafluoroethane), HFA 227
(1,1,1,2,3,3,3-heptafluoropropane, and mixtures thereof. The preferred
HFA is HFA134a. HFAs may be present in the formulation in an amount in
the range from 75 to 95% (w/w), preferably from 85 to 90% (w/w), wherein
% (w/w) means the amount by weight of the component, expressed as percent
with respect to the total weight of the composition.

[0023] The co-solvent incorporated into formulation of the present
invention has a higher polarity than that of the propellant and may
include one or more substances such as a pharmaceutically acceptable
alcohol, in particular ethanol, or a polyol such as propylene glycol or
polyethylene glycol.

[0024] Advantageously the co-solvent is selected from the group of lower
branched or linear alkyl (C1-C4) alcohols such as ethanol and
isopropyl alcohol. Preferably the co-solvent is ethanol.

[0025] The concentration of the co-solvent will vary depending on the
final concentration of the active ingredient in the formulation and on
the type of propellant. For example ethanol may be used in a
concentration comprised in the range from 5 to 25% (w/w), preferably from
8 to 20% (w/w), more preferably from 10 to 15% (w/w), wherein % (w/w)
means the amount by weight of the component, expressed as percent with
respect to the total weight of the composition. In one of the preferred
embodiments, the concentration of ethanol is 12% (w/w).

[0026] The ratio of propellant to co-solvent in the formulation is
preferably in the range 50:50 to 95:5 (w/w).

[0027] It is envisaged that HCl of a different molarity or alternative
inorganic acids (mineral acids) could substitute for 1M HCl in the
formulations of the invention. For instance, alternative acids could be
any pharmaceutically acceptable monoprotic or polyprotic acid, such as
(but not limited to): hydrogen halides (hydrochloric acid hydrobromic
acid, hydroiodic acid etc.) phosphoric acid, nitric acid, sulphuric acid,
and halogen oxoacids.

[0028] The pharmaceutically active components of the composition are
preferable completely and homogeneously dissolved in the mixture of
propellant and co-solvent, i.e. the composition is preferably a solution
formulation.

[0029] Optionally, the solution formulation compositions may comprise
other pharmaceutical excipients or additives known in the art. In
particular, the compositions of the present invention may comprise one or
more low volatility components. Low volatility components are useful in
order to increase the mass median aerodynamic diameter (MMAD) of the
aerosol particles upon actuation of the inhaler and/or to improve the
solubility of the active ingredient in the propellant/co-solvent mixture.

[0031] The amount of low volatility component may vary from 0.1 to 10%
w/w, preferably from 0.5 to 5% (w/w), more preferably between 1 and 2%
(w/w), wherein % (w/w) means the amount by weight of the component,
expressed as percent with respect to the total weight of the composition.

[0032] In one embodiment of the present invention, an amount of water
comprised between 0.005 and 0.5% (w/w), wherein % (w/w) means the amount
by weight of the component, expressed as percent with respect to the
total weight of the composition, may optionally be added to the
formulations in order to favourably affect the solubility of the active
ingredient without increasing the MMAD of the aerosol droplets upon
actuation.

[0033] Advantageously, the formulations of the present invention are free
of excipients (such as surfactants) other than the co-solvent, the
propellant, and a stabilizing amount of an acid.

[0034] The present invention also relates to a method for preparing a
pharmaceutical composition, comprising adding 1M HCl to a solution of
glycopyrronium bromide in HFA propellant and co-solvent, wherein the
amount of 1M HCl added is in the range of 0.005 to 1.0 μg per μl of
the final solution.

[0035] The pharmaceutical compositions of the present invention may
further comprise other, additional pharmaceutically active agents for
separate, sequential or simultaneous use. Optional additional
pharmaceutically active components of the composition include any known
in the art for prophylaxis or treatment of respiratory diseases and their
symptoms. Examples of these active components are: beta-2-agonists such
as formoterol, salbutamol, fenoterol, carmoterol (TA 2005), indacaterol,
milveterol, vilanterol (GSK 642444), terbultaline, salmeterol,
bitolterol, metaproterenol all in form of single stereoisomers or
mixtures thereof and salts thereof; corticosteroids such as beclometasone
dipropionate, fluticasone propionate, butixocort, mometasone furoate,
triamcinolone acetonide, budesonide and its 22R-epimer, ciclesonide,
flunisolide, loteprednol, and rofleponide; other anti-muscarinic drugs
such as methscopolamine, ipratropium bromide, oxitropium bromide and
tiotropium bromide; phosphodiesterase IV inhibitors such as: cilomilast,
roflumilast and tetomilast. Among these additional active components
formoterol fumarate is particularly preferred.

[0036] The compositions of the present invention can be inhaled from any
suitable MDI device known to the skilled person. Desired doses of the
individual pharmaceutically active components of the formulation are
dependent on the identity of the component and the type and severity of
the disease condition, but are preferably such that a therapeutic amount
of the active ingredient is delivered in one or two actuations. Generally
speaking, doses of active ingredient are in the range of about 0.5 μg
to 1000 μg per actuation, e.g. about 1 to 100 μg/actuation, and
sometimes about 5 to 50 μg/actuation. The skilled person in the field
is familiar with how to determine the appropriate dosage for each
individual pharmaceutically active ingredient.

[0037] With specific reference to glycopyrronium bromide, the preferred
dosage is about 0.5 to 100 μg per actuation, preferably about 1 to 40
μg per actuation, more preferably about 5 to 26 μg per actuation,
even more preferably 25 μg per actuation.

[0038] The pharmaceutical formulation of the present invention is filled
into pMDI devices known in the art. Said devices comprise a canister
fitted with a metering valve. Actuation of the metering valve allows a
small portion of the spray product to be released. Part or all of the
canister may be made of a metal, for example aluminium, aluminium alloy,
stainless steel or anodized aluminium. Alternatively the canister may be
a plastic can or a plastic-coated glass bottle.

[0039] The metal canisters may have part or all of the internal surfaces
lined with an inert organic coating. Examples of preferred coatings are
epoxy-phenol resins, perfluorinated polymers such as
perfluoroalkoxyalkane, perfluoroalkoxyalkylene, perfluoroalkylenes such
as poly-tetrafluoroethylene (Teflon), fluorinated-ethylene-propylene
(FEP), polyether sulfone (PES) or fluorinated-ethylene-propylene
polyether sulfone (FEP-PES) mixtures or combination thereof. Other
suitable coatings could be polyamide, polyimide, polyamideimide,
polyphenylene sulfide or their combinations.

[0040] In certain embodiments, canisters having the internal surface lined
with FEP-PES or Teflon may preferably be used.

[0041] In other particular embodiments, canisters made of stainless steel
may be used.

[0042] The container is closed with a metering valve for delivering a
daily therapeutically effective dose of the active ingredient. Generally,
the metering valve assembly comprises a ferrule having an aperture formed
therein, a body moulding attached to the ferrule which houses the
metering chamber, a stem consisting of a core and a core extension, an
inner- and an outer-seal around the metering chamber, a spring around the
core, and a gasket to prevent leakage of propellant through the valve.

[0043] The gasket seal and the seals around the metering valve may
comprise elastomeric material such as EPDM, chlorobutyl rubber,
bromobutyl rubber, butyl rubber, or neoprene. EPDM rubbers are
particularly preferred. The metering chamber, core and core extension are
manufactured using suitable materials such as stainless steel, polyesters
(e.g. polybutyleneterephthalate (PBT)), or acetals. The spring is
manufactured in stainless steel eventually including titanium. The
ferrule may be made of a metal, for example aluminum, aluminum alloy,
stainless steel or anodized aluminum. Suitable valves are available from
manufacturers such as Valois, Bespak plc and 3M-Neotechnic Ltd.

[0044] The pMDI is actuated by a metering valve capable of delivering a
volume of between 25 to 100 μl, preferably between 40 to 70 μl, and
optionally about 50 μl, or about 63 μl per actuation.

[0045] Each filled canister is conveniently fitted into a suitable
channeling device prior to use to form a metered dose inhaler for
administration of the medicament into the lungs of a patient. Suitable
channeling devices comprise, for example, a valve actuator and a
cylindrical or cone-like passage through which medicament may be
delivered from the filled canister via the metering valve to the mouth of
a patient e.g. a mouthpiece actuator.

[0046] In a typical arrangement, the valve stem is seated in a nozzle
block which has an orifice leading to an expansion chamber. The expansion
chamber has an exit orifice which extends into the mouthpiece. Actuator
(exit) orifices having a diameter in the range 0.15 to 0.45 mm and a
length from 0.30 to 1.7 mm are generally suitable. Preferably an orifice
having a diameter from 0.2 to 0.44 mm is used, e.g. 0.22, 0.25, 0.30,
0.33 or 0.42 mm.

[0047] In certain embodiments of the present invention, it may be useful
to utilize actuator orifices having a diameter ranging from 0.10 to 0.22
mm, in particular from 0.12 to 0.18 mm, such as those described in WO
03/053501. The use of said fine orifices may also increase the duration
of the cloud generation and hence, may facilitate the coordination of the
cloud generation with the slow inspiration of the patient.

[0048] In case the ingress of water into the formulation is to be avoided,
it may be desired to overwrap the MDI product in a flexible package
capable of resisting water ingress. It may also be desirable to
incorporate a material within the packaging which is able to adsorb any
propellant and co-solvent which may leak from the canister (e.g. a
molecular sieve).

[0049] Optionally, the MDI device filled with the formulation of the
present invention may be utilized together with suitable auxiliary
devices favoring the correct use of the inhaler. Said auxiliary devices
are commercially available and, depending on their shape and size, are
known as "spacers", "reservoirs" or "expansion chambers". Volumatic®
is, for instance, one of the most widely known and used reservoirs, while
Aerochamber® is one of the most widely used and known spacers. A
suitable expansion chamber is reported for example in WO 01/49350.

[0050] The formulation of the present invention may also be used with
common pressurized breath-activated inhalers such as those known with the
registered names of Easi-Breathe® and Autohaler®.

[0051] The efficacy of an MDI device is a function of the dose deposited
at the appropriate site in the lungs. Deposition is affected by the
aerodynamic particle size distribution of the formulation which may be
characterized in vitro through several parameters.

[0052] The aerodynamic particle size distribution of the formulation of
the invention may be characterized using a Cascade Impactor according to
the procedure described in the European Pharmacopoeia 6th edition,
2009 (6.5), part 2.09.18. An Apparatus E, operating at a flow rate range
of 30 litres/minute to 100 litres/minute or an Apparatus D-Andersen
Cascade Impactor (ACI)-, operating at a flow rate of 28.3 l/minute, may
be utilized. Deposition of the drug on each ACI plate is determined by
high performance liquid chromatography (HPLC).

[0053] The following parameters of the particles emitted by a pressurized
MDI may be determined: [0054] i) mass median aerodynamic diameter
(MMAD) is the diameter around which the mass aerodynamic diameters of the
emitted particles are distributed equally; [0055] ii) delivered dose is
calculated from the cumulative deposition in the ACI, divided by the
number of actuations per experiment; [0056] iii) respirable dose (fine
particle dose=FPD) is obtained from the deposition from Stages 3 (S3) to
filter (AF) of the ACI, corresponding to particles of diameter
≦4.7 microns, divided by the number of actuations per experiment;
[0057] iv) respirable fraction (fine particle fraction=FPF) which is the
percent ratio between the respirable dose and the delivered dose; and
[0058] v) "superfine" dose is obtained from the deposition from Stages 6
(S6) to filter, corresponding to particles of diameter ≦1.1
microns, divided by the number of actuations per experiment.

[0059] The solutions of the present invention are capable of providing,
upon actuation of the pMDI device in which they are contained, a total
FPF higher than 40%, preferably higher than 50%, more preferably higher
than 60%.

[0060] Moreover, the formulations of the present invention are capable of
providing, on actuation, a fraction higher than or equal to 30% of
emitted particles of diameter equal to or less than 1.1 microns as
defined by the content stages S6-AF of an Andersen Cascade Impactor,
relative to the total fine particle dose collected in the stages S3-AF of
the impactor. Preferably the fraction of emitted particles of diameter
equal to or less than 1.1 microns is higher than or equal to 40%, more
preferably higher than 50%, even more preferably higher than 60%, most
preferably higher than 70%.

[0061] According to a further aspect of the present invention there is
provided a method of filling an aerosol inhaler with a composition of the
present invention. Conventional bulk manufacturing methods and machinery
well known to those skilled in the art of pharmaceutical aerosol
manufacture may be employed for the preparation of large-scale batches
for the commercial production of filled canisters.

[0062] The method comprises: [0063] a) preparing a solution comprising
glycopyrronium bromide, a co-solvent (e.g. ethanol), a mineral acid, a
propellant comprising a HFA and optionally a low volatility component at
a temperature from -50 to -60° C. at which the solution does not
vaporize; [0064] b) cold filling the inhaler with the prepared solution;
and [0065] c) placing the valve onto the can and crimping.

[0066] An alternative method comprises: [0067] a) preparing a solution
comprising glycopyrronium bromide, a co-solvent (e.g. ethanol), a mineral
acid, and optionally a low volatility component; [0068] b) filling the
open can with the bulk solution; [0069] c) placing the valve onto the can
and (vacuum) crimping; and [0070] d) pressure-filling the can with HFA
propellant through the valve.

[0071] A further alternative method comprises: [0072] a) preparing a
solution comprising glycopyrronium bromide, a co-solvent (e.g. ethanol),
a mineral acid, an optional low volatility component and HFA propellant
using a pressurised vessel: [0073] b) placing the valve onto the empty
can and crimping; and [0074] c) pressure-filling the can with the final
solution formulation through the valve.

[0075] The packaged formulations of the present invention are stable for
extended periods of time when stored under normal conditions of
temperature and humidity. In a preferred embodiment, the packaged
formulations are stable for at least 6 months at 25° C. and 60%
RH, more preferably for at least 1 year, most preferably for at least 2
years. Stability is assessed by measuring content of residual active
ingredient. A "stable" formulation as defined herein means one retaining
at least about 85%, preferably at least about 90%, and most preferably at
least about 95% of residual content of each active ingredient at a given
time point, as measured by HPLC-UV VIS.

[0076] The optimized stable formulations meet the specifications required
by the ICH Guideline Q1B or CPMP/QWP/122/02 Rev.1 relevant for drug
product stability testing for the purposes of drug registration.

[0077] The product of the present invention may be used for prophylactic
purposes or for symptomatic relief of a wide range of respiratory
disorders, such as asthma of all types and chronic obstructive pulmonary
disease (COPD).

[0078] Other respiratory disorders for which use of the pharmaceutical
compositions of the present invention may be beneficial are those
characterized by obstruction of the peripheral airways as a result of
inflammation and presence of mucus, such as chronic obstructive
bronchiolitis, chronic bronchitis, emphysema, acute lung injury (ALI),
cystic fibrosis, rhinitis, and adult or acute respiratory distress
syndrome (ARDS).

[0079] Other features of the invention will become apparent in the course
of the following descriptions of exemplary embodiments which are given
for illustration of the invention and are not intended to be limiting
thereof.

EXAMPLES

Example 1

Glycopyrronium Bromide Stability During Storage with or without Acid
Addition

[0080] Solution formulations were prepared with the compositions shown in
Table 1.

[0081] The samples containing acid were formulated by the addition of 1M
HCl in an amount corresponding to 0.222 μg/μl of the solution. The
solution was filled into canisters which were stored inverted under
different conditions: 5°; 25° C./60% RH; 30° C./75%
RH; 40° C./75% RH. The samples were analyzed chromatographically
for glycopyrronium bromide content after 1 to 3 months of storage and
after 6 months storage only for 5°; 25° C./60% RH. The
results are reported in the following Table 2.

[0082] As shown in Table 2, GLY was relatively unstable when stored under
suboptimal conditions. After 3 months at 40° C./75% RH, the
content of GLY in the samples decreased to about 80%. However, in the
presence of acid there was no significant degradation of GLY at 3 months,
irrespective of the storage conditions. The obtained data at 5°;
25° C./60% RH show that in presence of acid the product can be
stored both in normal and accelerated conditions, whereas without acid it
is not possible to store it at 25° C./60% RH.

Example 2

Glycopyrronium Bromide Stability During Storage with Different Amount of
HCl

[0083] Solution formulations were prepared with a composition
corresponding to that of Example 1, Table 1, added with the following
different amounts of 1 M HCl.

[0084] The solutions were filled into conventional aluminium canisters
provided with EPDM valves which were stored inverted for 1 month at
40° C./75% RH. The samples were analyzed chromatographically for
glycopyrronium bromide content, and the values are the mean values from
three cans.

[0085] No stability issues were found for the whole range of acid
concentrations.

[0086] The residual glycopyrronium bromide content ranged from
95.9±0.5% to 101.9±2.4% with respect to the content at time 0, and
the total degradation product ranged from 0.8±0.1% to 3.7±1.0% of
the total composition. Moreover when the concentrations of the acid was
lower than 0.187 μg/μl or higher than 0.743 μg/μl, less
residual active ingredient, higher levels of degradation products, and
more variability of their levels were obtained.

[0087] Therefore, stable glycopyrronium bromide HFA solution formulations
may be obtained by using an amount of 1M hydrochloric acid (HCl) in the
range of 0.005 to 1.0 μg/μl, preferably of 0.099 to 0.74
μg/μl, and more preferably 0.18 to 0.32 μg/μl.

[0088] Where a numerical limit or range is stated herein, the endpoints
are included. Also, all values and subranges within a numerical limit or
range are specifically included as if explicitly written out.

[0089] Obviously, numerous modifications and variations of the present
invention are possible in light of the above teachings. It is therefore
to be understood that, within the scope of the appended claims, the
invention may be practiced otherwise than as specifically described
herein.

[0090] All patents and other references mentioned above are incorporated
in full herein by this reference, the same as if set forth at length.